Bone is a complex system whose critical function is to be sufficiently stiff and strong to support the physical forces associated with daily activities. Understanding how genetic and environmental variants compromise this function is critical to fully understanding why certain individuals are more susceptible to fracturing. Trabecular and cortical traits both contribute to load bearing of corticocancellous structures, and variation in the relative proportion of these two tissue types is a critical determinant of fracture risk. However, the cause of variation in the relative proportion of cortical and trabecular tissues among individuals is not well understood. Based on our own work examining functional relationships in mouse and human long bone, we postulate that variation in cortical and trabecular traits arises from an interplay between functional adaptation (Wolff's Law) and genetic variants affecting bone size. We propose to determine how genetic variants affecting vertebral size, a critical determinant of fracture risk, are compensated by specific functional interactions among cortical and trabecular traits. We hypothesize that genetic variation in trabecular bone mass and architecture depends on the degree of load sharing arising from genetic variants affecting cortical size and quality. Further, we propose to determine how the functional interactions among cortical and trabecular traits maintain strength with aging. Because phenotypic covariation gives rise to genetically varying sets of adult traits, we also test the hypothesis that certain adult trait sets will be more resistant to bone loss and better able to maintain strength with aging. We will test these hypotheses using a panel of AXB/BXA Recombinant Inbred (RI) Mouse Strains, which is a powerful model to study compensatory relationships among traits within the normal (i.e., non-pathological) range of genetic variability. In Aim I, we use Path Analysis to test whether trabecular and cortical traits show a compensatory relationship, and identify the trait interactions that compensate for genetic variants affecting adult vertebral size. In Aim II, we determine how phenotypic covariation arises during growth. In Aim III, we assess the impact of phenotypic covariation on the ability of bone cells to maintain stiffness and strength with aging. Finally, we test how sex affects phenotypic covariation throughout growth and aging. This systems analysis, which examines the relationship among traits in the context of functionality, will provide new insight into the genetic basis of fracture susceptibility. PUBLIC HEALTH RELEVANCE: We propose to determine how functional interactions among cortical and trabecular traits compensate for genetic variants affecting vertebral size and contribute to fracture susceptibility. We use genetically randomized inbred mouse strains to determine how compensatory trait interactions arising during growth lead to varying sets of adult traits expressing different abilities to maintain strength with aging. This systems analysis, which examines the relationship among traits in the context of functionality, will provide new insight into the genetic basis of fracture susceptibility.